Hidden FDA Reports Detail Harm Caused By Scores Of Medical Devices

The Food and Drug Administration has let medical device companies file reports of injuries and malfunctions outside a widely scrutinized public database, which leave doctors and medical sleuths in the dark

Kaiser Health News senior correspondent Christina Jewett explains how she investigated a Food and Drug Administration database where medical device makers report malfunctions and patient injuries, skirting the public record. Because the cache of information is buried deep within the agency, it’s often hard for physicians, researchers and patient safety advocates to access the information.

How one scientist averted a national health crisis

Dr Frances Oldham Kelsey : 20th-century American heroine for her role in the Thalidomide case

In 1960, Frances Kelsey was one of the Food and Drug Administration’s newest recruits. Before the year was out, she would begin a fight that would save thousands of lives — though no one knew it at the time.

  • Andrea Tone explains how Kelsey was able to prevent a massive national public health tragedy by privileging facts over opinions, and patience over shortcuts.
  • Video published on 7 June 2018 by TED-Ed.

Why Dissent Matters

Because Some People See Things the Rest of Us Miss

The thalidomide tragedy was averted in the United States because Dr. Kelsey, alone and in the face of fierce opposition, did her job. Her perspective was educated, fresh and unique. If there had been no thalidomide crisis, the United States, with the rest of the world following, would still at some time have brought pharmaceutical regulation into the 20th century. But thalidomide created one of those moments when something had to be done. It could not be ignored in 1961-62, and it led immediately to a better and stronger regulatory system. Maybe someone else would have stopped thalidomide in the United States had Dr. Kelsey not been assigned the NDA, but, interestingly, no one else stopped it anywhere else until it was too late. Dr. Kelsey was the only person in the entire world who said no. She said no to a bad drug application, she said no to an overbearing pharmaceutical company and she said no to vested interests who put profits first. She was one brave dissenter. In the end, the question is not what made Frances Kelsey, but why aren’t there more like her?

Because Some People See Things the Rest of Us Miss

The nature writer Rachel Carson identified an emerging environmental disaster and pulled the fire alarm. Public protests, individual dissenters, judges, and juries can change the world – and they do.

A wide-ranging and provocative work on controversial subjects, Why Dissent Matters tells a story of dissent and dissenters – people who have been attacked, bullied, ostracized, jailed, and, sometimes when it is all over, celebrated.

William Kaplan shows that dissent is noisy, messy, inconvenient, and almost always time-consuming, but that suppressing it is usually a mistake – it’s bad for the dissenter but worse for the rest of us. Drawing attention to the voices behind international protests such as Occupy Wall Street and Boycott, Divest, and Sanction, he contends that we don’t have to do what dissenters want, but we should listen to what they say. Our problems are not going away. There will always be abuses of power to confront, wrongs to right, and new opportunities for dissenting voices to say, “Stop, listen to me.” Why Dissent Matters may well lead to a different and more just future.

Read This is Dr. Frances Kelsey’s story, the globe and mail, MAY 11, 2017.

Drugs stalled at FDA far more likely to have unpublished trials than licensed ones: 46% vs 10%

Nonpublication of Trial Results for New Neurological Drugs: A Systematic Review

May 2017 Study Abstract

To evaluate nonpublication rates among trials of new successful and unsuccessful neurological drugs – A Systematic Review.

‘Licensed’ drugs consisted of all novel agents receiving FDA licensure 2005 to 2012 inclusive in seven neurological disorders. ‘Stalled’ drugs included all experimental agents tested in the same domains that had at least one completed phase III trial in the same timeframe but failed to receive FDA approval. Trials of these drugs were included in our sample if their primary outcome collection occurred before October 1, 2010. We determined the publication status of eligible trials using searches of clinicaltrials.gov, Google Scholar, PubMed, Embase, sponsor websites, and direct electronic query of trial contacts and sponsors. The primary outcome was time to journal publication (or results reporting in other media) after study completion.

The adjusted hazard ratio for publication was 1.79 (95% confidence interval 1.20 to 2.67) in favour of licensed drugs. Based on the criteria for nonpublication in this report, 14,092 and 33,882 volunteers participated in unpublished trials of licensed and stalled neurological drugs, respectively. Result data were not publicly available in any form for 10% (16/163) and 46% (94/203) of trials of licensed and stalled drugs, respectively.

Results of trials for stalled drugs are heavily underreported. This deprives research and care communities of evidence about pathophysiology, drug class effects, and the value of surrogate endpoints in trials.

Nearly one-third of new drugs have safety concerns after FDA approval

Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010

How often are safety concerns raised about a drug after it’s been approved by the FDA?.

Nicholas Downing, MD, of the Department of Medicine at Brigham and Women’s Hospital, and colleagues have found that for drugs approved between 2001 and 2010, nearly 1 in 3 had a postmarket safety event.

The team defines postmarket safety events as those that lead to either withdrawal from the market due to safety concerns, a boxed warning or FDA issuance of a safety communication.

They found that of 222 novel therapeutics the FDA approved during this time period, three were withdrawn, 61 received boxed warnings and 59 elicited safety communications.

Key Points

Are characteristics of novel therapeutics known at the time of US Food and Drug Administration (FDA) approval associated with postmarket safety events, including withdrawal, boxed warnings, and safety communications?

Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 71 (32.0%) were affected by a postmarket safety event. Postmarket safety events were more frequent among biologics, therapeutics indicated for the treatment of psychiatric disease, those receiving accelerated approval, and those with near–regulatory deadline approval.

Postmarket safety events are common after FDA approval, highlighting the importance of continuous monitoring of the safety of novel therapeutics throughout their life cycle.

2017 Study Abstract

Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making.

To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk.

Design and Setting
Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017.

Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time.

Main Outcomes and Measures
A composite of

  1. withdrawals due to safety concerns,
  2. FDA issuance of incremental boxed warnings added in the postmarket period,
  3. and FDA issuance of safety communications.

From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02).

Conclusions and Relevance
Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near–regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.

Postmarketing studies after the FDA approves drugs on limited evidence

Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review


In the US, the Food and Drug Administration determines whether a new drug is sufficiently safe and effective to be made available to doctors for use by patients. To do this, it must find a balance between requiring sufficient high quality clinical evidence from premarket evaluation and allowing promising new drugs to enter the marketplace quickly with continued evaluation after approval. The FDA maintains a “usual requirement” of “more than one” well controlled clinical trial that independently proves a drug’s efficacy. However, it also describes several situations in which fewer trials or studies with non-clinical outcomes, such as surrogate markers of disease, might suffice for premarket evaluation. Thus, FDA approval is binary, but the clinical trial evidence that forms the basis of the FDA’s decision varies widely.


Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review, The BMJ, doi.org/10.1136/bmj.j1680, 03 May 2017.

Image credit @bmj_latest.

To characterize the prospective controlled clinical studies for all novel drugs that were initially approved by the Food and Drug Administration on the basis of limited evidence.

Systematic review.

Data sources
Drugs@FDA database and PubMed.

Study inclusion
All prospective controlled clinical studies published after approval for all novel drugs initially approved by the FDA between 2005 and 2012 on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease as primary endpoints, or both.

Between 2005 and 2012 the FDA approved 117 novel drugs for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials). We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4-8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators—67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials—and examined surrogate markers of efficacy as primary endpoints—51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0-2) for indications approved on the basis of a single pivotal trial, 3 (1-8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0-2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0-509), 533 (122-3633), and 38 (0-666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively.

The quantity and quality of postapproval clinical evidence varied substantially for novel drugs approved by the FDA on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both. Fewer than 10% of approved indications had one or more published randomized controlled, double blind study showing superior efficacy based on clinical outcomes that examined the same indication for which the drug was first approved by the FDA after a median of 5.5 years after approval. These findings should inform both clinical decision making and regulatory policy regarding requirements before and after approval of novel drugs.

Addyi Flibanserin HSDD Drug has Limited Benefits and produces Negative Effects

‘Female Viagra’ safety, efficacy questioned

The safety and efficacy of flibanserin, a controversial drug aimed at increasing female libido, return to the spotlight as a systematic review study highlights the results of unpublished trials. The “female viagra” drug, finally approved last year by the US Food and Drug Administration has limited benefits and produces negative effects,


Efficacy and Safety of Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Women, A Systematic Review and Meta-Analysis, JAMA Intern Med. doi:10.1001/jamainternmed.2015.8565 2497781, February 29, 2016.

In August 2015, the US Food and Drug Administration (FDA) approved flibanserin as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women, despite concern about suboptimal risk-benefit trade-offs.

To conduct a systematic review and meta-analysis of randomized clinical trials assessing efficacy and safety of flibanserin for the treatment of HSDD in women.

Data Sources
Medical databases (among others, Embase, Medline, Psycinfo) and trial registries were searched from inception to June 17, 2015. Reference lists of retrieved studies were searched for additional publications.

Study Selection
Randomized clinical trials assessing treatment effects of flibanserin in premenopausal and postmenopausal women were eligible. No age, language, or date restrictions were applied. Abstract and full-text selection was done by 2 independent reviewers.

Data Extraction and Synthesis
Data were extracted by one reviewer and checked by a second reviewer. Results were pooled using 2 approaches depending on the blinding risk of bias.

Main Outcomes and Measures
Primary efficacy outcomes included number of satisfying sexual events (SSEs), eDiary sexual desire, and Female Sexual Function Index (FSFI) desire. Safety outcomes included, among others, 4 common adverse events (AEs): dizziness, somnolence, nausea, and fatigue.

Five published and 3 unpublished studies including 5914 women were included. Pooled mean differences for SSE change from baseline were 0.49 (95% CI, 0.32-0.67) between 100-mg flibanserin and placebo, 1.63 (95% CI, 0.45-2.82) for eDiary desire, and 0.27 (95% CI, 0.17-0.38) for FSFI desire. The risk ratio for study discontinuation due to AEs was 2.19 (95% CI, 1.50-3.20). The risk ratio for dizziness was 4.00 (95% CI, 2.56-6.27) in flibanserin vs placebo, 3.97 (95% CI, 3.01-5.24) for somnolence, 2.35 (95% CI, 1.85-2.98) for nausea, and 1.64 (95% CI, 1.27-2.13) for fatigue. Women’s mean global impression of improvement scores indicated minimal improvement to no change.

‘Female Viagra’ safety, efficacy questioned in new study, medicalnewstoday, February 29, 2016.

Conclusions and Relevance
Treatment with flibanserin, on average, resulted in one-half additional SSE per month while statistically and clinically significantly increasing the risk of dizziness, somnolence, nausea, and fatigue. Overall, the quality of the evidence was graded as very low. Before flibanserin can be recommended in guidelines and clinical practice, future studies should include women from diverse populations, particularly women with comorbidities, medication use, and surgical menopause.

Clinical trial registration, reporting, publication and FDAAA compliance: unacceptably low

More drug trial data should be online

image of clinical-trials
Trial disclosures for new drugs remain below legal and ethics standards, with wide variation in practices among drugs and their sponsors. Clinical Trials by Sanofi Pasteur.

2015 Study Abstract

Leading clinical research authorities are calling for more aggressive enforcement of requirements for public reporting of the results of experimental drug trials, in response to a recent STAT investigation that found widespread failures by eminent universities and pharmaceutical firms to file data on their clinical trials.

To evaluate clinical trial registration, reporting and publication rates for new drugs by: (1) legal requirements and (2) the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge.

Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration (FDA) for drugs approved in 2012, sponsored by large biopharmaceutical companies.

Data sources
Information from Drugs@FDA, ClinicalTrials.gov, MEDLINE-indexed journals and drug company communications.

Main outcome measures
Clinical trial registration and results reporting in ClinicalTrials.gov, publication in the medical literature, and compliance with the 2007 FDA Amendments Acts (FDAAA), analysed on the drug level.

The FDA approved 15 drugs sponsored by 10 large companies in 2012. We identified 318 relevant trials involving 99 599 research participants. Per drug, a median of 57% (IQR 32–83%) of trials were registered, 20% (IQR 12–28%) reported results in ClinicalTrials.gov, 56% (IQR 41–83%) were published, and 65% (IQR 41–83%) were either published or reported results. Almost half of all reviewed drugs had at least one undisclosed phase II or III trial. Per drug, a median of 17% (IQR 8–20%) of trials supporting FDA approvals were subject to FDAAA mandated public disclosure; of these, a median of 67% (IQR 0–100%) were FDAAA-compliant. 68% of research participants (67 629 of 99 599) participated in FDAAA-subject trials, with 51% (33 405 of 67 629) enrolled in non-compliant trials. Transparency varied widely among companies.

Trial disclosures for new drugs remain below legal and ethics standards, with wide variation in practices among drugs and their sponsors. Best practices are emerging. 2 of our 10 reviewed companies disclosed all trials and complied with legal disclosure requirements for their 2012 approved drugs. Ranking new drugs on transparency criteria may improve compliance with legal and ethics standards and the quality of medical knowledge.

Sources and more information
  • Health officials call for better enforcement on clinical trial reporting, STAT news, DECEMBER 22, 2015.
  • Do drug-firm ties affect researchers’ reporting of study results?, STAT news, DECEMBER 18, 2015.
  • More drug trial data should be online, bostonglobe, DECEMBER 14, 2015.
  • Top institutions not reporting clinical trial results as required, STAT news, DECEMBER 13, 2015.
  • Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012, BMJ Open doi:10.1136/bmjopen-2015-009758, 12 November 2015.

Support FDA’s Proposal to Collect More Data on Antibiotics and Distribution Information in Livestock

Livestock specific data would help us better understand how drug sales relate to antibiotic resistance on the farm that may in turn affect human health

image of pigs
FDA released a proposed rule to collect estimates from drug companies of antibiotics sold for use in pigs, cows, chickens, and turkeys.

U.S. FDA, For Industry,
Animal Drug User Fee Act (ADUFA) 05/19/2015

In May 2015, the FDA issued a proposed rule to obtain more detailed information about antimicrobials sold or distributed for use in food-producing animals by including estimates of sales data by species. The additional data would improve understanding about the extent to which antimicrobials are sold or distributed for use in major food-producing species and help the FDA further target its efforts to ensure judicious use of medically important antimicrobials. It would also assist the agency in measuring the effectiveness of those efforts.

The U.S. Food and Drug Administration needs to hear from people like you

The proposed rule, if finalized, would require animal drug sponsors to submit species-specific estimates of antimicrobial sales for cattle, swine, chickens, and turkeys. The proposed rule also includes a provision to improve the timeliness of FDA’s annual summary report of these sales data by requiring the FDA to publish its annual summary report of antimicrobial sales and distribution information by December 31 of the following year.

Sources and more information
  • FDA proposes rule to collect antimicrobial sales and distribution data by animal species, Additional data to help Agency further target efforts to ensure judicious use of medically important antimicrobials, FDA News, May 19, 2015.
  • Support FDA’s Proposal to Collect More Data on Antibiotics in Agriculture!, The Pew Charitable Trusts.
  • Support FDA’s Call for Data on Antibiotics in Agriculture!, ecocenter, August 12, 2015.

Why off-label marketing is irresistible to Big Pharma

If off-label marketing is ‘speech,’ why even have the FDA?

This post content is written by Martha Rosenberg and published by Reporting on Health, a nonprofit, nonpartisan and educational offering resources & community for journalists covering health

It has always been legal for U.S. doctors to prescribe drugs for off-label uses but marketing of off-label uses has been illegal. Image via pharmamkting.blogspot.

It has always been legal for U.S. doctors to prescribe drugs for off-label uses but marketing of off-label uses has been illegal. In August, U.S. District Judge Paul A. Engelmayer ruled that the First Amendment allows a drug company to “engage in truthful and non-misleading speech promoting the off-label use” of drugs and that the FDA cannot bar such “speech.” The ruling, pertaining to the drug Amarin, which targets high triglyceride levels, is likely to be appealed and only applies to the 2nd U.S. Circuit Court of Appeals, which includes New York, Connecticut and Vermont. But patients had better beware.

Off-label marketing is irresistible to Big Pharma because it saves years and millions spent on clinical trials which may not assure FDA approval anyway. It allows drug companies to circumvent the pesky and slow FDA altogether and get on with the business of making money– bringing their sales pitch to doctors and patients directly. Almost all major drug companies—GSK, Eli Lilly, Abbott, AstraZeneca, Pfizer, Johnson & Johnson, Amgen, Allergen, Bristol-Myers Squibb, Cephalon, Novartis and Purdue (which makes Oxycontin)––have agreed to huge settlements which include charges of off-label marketing.

In court-released confidential memos, Pfizer (then Parke-Davis) admits why it chose to off-label market Neurontin (only approved for postherpetic neuralgia and adjunctive seizure therapy) for the unapproved indication of bipolar disorder. “The U.S. market for Bipolar Disorders is an attractive commercial opportunity that warrants clinical development of Neurontin. Based on the current patent situation, an investment in full clinical development is not recommended at this time since completion of two pivotal trials and regulatory filing and approval would occur close to patent expiration,” says the memo. Translation: It would take too long to get legal approval—our patent would expire. Instead, says the memo, “it is recommended to implement only an exploratory study in outpatients with bipolar disorders with the results highlighted through a peer reviewed publication.” Translation: Let’s not do the studies and plant some info in medical journals that looks like we did.

Pfizer paid a $430 million fine and signed a corporate integrity agreement for off-label marketing of Neurontin which was linked to wrongful deaths and suicides. But that did not stop Pfizer from off-label marketing Lyrica, sometimes called “son of Neurontin,” soon afterward. Who can say incorrigible?

Nor did Eli Lilly’s guilty plea in 2009 to the off-label promotion of the antipsychotic Zyprexa deter it from requesting permission from the FDA to market Zyprexa to children three months later. The FDA said—yes! At the same time, Pfizer and AstraZeneca also requested permission to market their antipsychotics, Geodon and Seroquel respectively, to kids though both agreed to off-label marketing those exact drugs months later.

Another off-label marketing scheme centered around the selective estrogen receptor modulator Evista. Eli Lilly, its manufacturer, had noted fewer incidences of breast cancer in an Evista trial and wanted to market it not just for its approved treatment of prevention of osteoporosis but for prevention of breast cancer. A group of doctors told Lilly the anticancer marketing claims were “an egregious stretch” and that Evista’s high risk of stroke canceled out any anticancer benefits.

Undaunted, Lilly armed 1000 of its drug reps with an off-label Evista sales plan to sell the unapproved use of breast cancer prevention. Drug reps were told to hide a disclosure page that said, “The effectiveness of [Evista] in reducing the risk of breast cancer has not yet been established,” and “All of the authors were either employees or paid consultants of Eli Lilly at the time this article was written,” according to the Department of Justice.

Lilly was charged with a violation of the Food, Drug, and Cosmetic Act and ordered to pay a $36 million settlement for the off-label marketing. But Evista did receive approval to reduce the “risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer.” The problem was the drug, marketed so freely for off-label uses, was far from safe. Prescribing information warned “Serious and life-threatening side effects can occur while taking EVISTA” and ads warned about “death due to stroke.” Its effectiveness was also not impressive. Patients were warned that Evista doesn’t “completely prevent breast cancer,” and “Breast examinations and mammograms should be done before starting Evista and regularly thereafter.”

Clearly, forgiveness is cheaper than permission for drug makers who consider such settlements the cost of doing business. But are drug sales pitches really “speech?” Can a “truthful and not misleading” determination really be made by the for-profit company selling the product? If drug companies’ product claims are protected under the First Amendment and they can sell directly to doctors and patients why even have an FDA?

Over 50 years ago, Big Pharma was also annoyed with the slow-paced FDA whose efforts to ensure drugs were safe cut into profits. One company even complained to an FDA official’s bosses that she was a petty bureaucrat. The company made thalidomide.